USP38 Inhibits Type I Interferon Signaling by Editing TBK1 Ubiquitination through NLRP4 Signalosome

Meng Lin; Zhiyao Zhao; Zhifen Yang; Qingcai Meng; Peng Tan; Weihong Xie; Yunfei Qin; Rong-Fu Wang; Jun Cui

doi:10.1016/j.molcel.2016.08.029

USP38 Inhibits Type I Interferon Signaling by Editing TBK1 Ubiquitination through NLRP4 Signalosome

Mol Cell. 2016 Oct 20;64(2):267-281. doi: 10.1016/j.molcel.2016.08.029. Epub 2016 Sep 29.

Authors

Meng Lin¹, Zhiyao Zhao², Zhifen Yang³, Qingcai Meng², Peng Tan⁴, Weihong Xie³, Yunfei Qin², Rong-Fu Wang⁵, Jun Cui⁶

Affiliations

¹ Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
² Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
³ Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
⁴ Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Houston, TX 77030, USA.
⁵ Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA; Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Houston, TX 77030, USA. Electronic address: [email protected].
⁶ Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].

PMID: 27692986
DOI: 10.1016/j.molcel.2016.08.029

Abstract

TBK1 is a component of the type I interferon (IFN) signaling pathway, yet the mechanisms controlling its activity and degradation remain poorly understood. Here we report that USP38 negatively regulates type I IFN signaling by targeting the active form of TBK1 for degradation in vitro and in vivo. USP38 specifically cleaves K33-linked poly-ubiquitin chains from TBK1 at Lys670, and it allows for subsequent K48-linked ubiquitination at the same position mediated by DTX4 and TRIP. Knockdown or knockout of USP38 increases K33-linked ubiquitination, but it abrogates K48-linked ubiquitination and degradation of TBK1, thus enhancing type I IFN signaling. Our findings identify an essential role for USP38 in negatively regulating type I IFN signaling, and they provide insights into the mechanisms by which USP38 regulates TBK1 ubiquitination through the NLRP4 signalosome.

Keywords: K33 ubiquitination; TBK1 degradation; TBK1 ubiquitination; USP38 deubiquitination; innate immune signaling; type I interferon response.

MeSH terms

Adaptor Proteins, Signal Transducing
Amino Acid Sequence
Animals
Bone Marrow Cells / immunology
Bone Marrow Cells / metabolism
Bone Marrow Cells / virology
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology
DNA-Binding Proteins / metabolism
Eukaryotic Initiation Factors / genetics
Eukaryotic Initiation Factors / immunology
Eukaryotic Initiation Factors / metabolism
Gene Expression Regulation
Herpesvirus 1, Human / growth & development
Herpesvirus 1, Human / immunology
Host-Pathogen Interactions
Immunity, Innate*
Interferon Type I / genetics
Interferon Type I / immunology
Interferon Type I / metabolism*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / immunology
Intracellular Signaling Peptides and Proteins / metabolism
Macrophages / immunology
Macrophages / metabolism*
Macrophages / virology
Mice
Mice, Knockout
Phosphorylation
Polyubiquitin / genetics
Polyubiquitin / immunology
Polyubiquitin / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / immunology
Protein Serine-Threonine Kinases / metabolism*
Proteins / genetics
Proteins / immunology
Proteins / metabolism*
Signal Transduction / immunology*
Ubiquitin-Specific Proteases / genetics
Ubiquitin-Specific Proteases / immunology
Ubiquitin-Specific Proteases / metabolism*
Ubiquitination
Vesiculovirus / growth & development
Vesiculovirus / immunology

Substances

Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
Eukaryotic Initiation Factors
Interferon Type I
Intracellular Signaling Peptides and Proteins
Nlrp4 protein, mouse
Proteins
TRIP-1 protein, mouse
ribonuclease inhibitor protein, mouse
Polyubiquitin
Tbk1 protein, mouse
Protein Serine-Threonine Kinases
Ubiquitin-Specific Proteases
Usp38 protein, mouse